WO2008113929A1 - Pharmaceutical composition containing phloroglucinol and paracetamol - Google Patents

Pharmaceutical composition containing phloroglucinol and paracetamol Download PDF

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Publication number
WO2008113929A1
WO2008113929A1 PCT/FR2008/050263 FR2008050263W WO2008113929A1 WO 2008113929 A1 WO2008113929 A1 WO 2008113929A1 FR 2008050263 W FR2008050263 W FR 2008050263W WO 2008113929 A1 WO2008113929 A1 WO 2008113929A1
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Prior art keywords
pharmaceutical composition
paracetamol
phloroglucinol
composition according
oral
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PCT/FR2008/050263
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French (fr)
Inventor
Jean-Jacques Serrano
Claudette Serrano
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Promindus (Actions Promotionnelles Dans L'industrie Et Le Commerce)
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Priority to CA2678042A priority Critical patent/CA2678042C/en
Priority to US12/527,592 priority patent/US8148425B2/en
Priority to BRPI0810057-8A2A priority patent/BRPI0810057A2/en
Priority to EP08762111A priority patent/EP2120901A1/en
Priority to MX2009008813A priority patent/MX2009008813A/en
Publication of WO2008113929A1 publication Critical patent/WO2008113929A1/en
Priority to MA32162A priority patent/MA31227B1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • the present invention relates to a pharmaceutical composition containing an antispasmodic (phoroglucinol) and an analgesic (paracetamoi).
  • Said composition suitable for oral or rectal administration, is particularly effective in antispasmodic therapy.
  • Spasm is an involuntary contraction, sudden, intense and very painful. It can be of renal origin in the case of renal colic, of hepatic origin in the case of hepatic colic, of intestinal origin in cases of intestinal spasm and spasmodic colitis, of gynecological origin in the case of dysmenorrhea.
  • spasm is accompanied by extremely intense and persistent pain.
  • antispasmodic There are two types of antispasmodic:
  • neurotropic antispasmodics such as atropine and its derivatives, scopolamine, quaternary ammoniums such as tiemonium iodide, butylhyoscine bromide ... and
  • musculotropic antispasmodics such as papaverine, mebevirine, trimebutine, pinaverium bromide, phloroglucinol and derivatives thereof
  • Neurotropic antispasmodics are less used because of the adverse effects that result from their antimuscarinic pharmacological action. Indeed, muscarinic receptors are very widely distributed in a variety of organs and peripheral and central tissues. Thus, a desired pharmacological action, for instance on intestinal peristalsis, is in most cases accompanied by undesirable effects on salivary secretion, the heart, the respiratory system, urogenital system. Moreover, said neurotropic antispasmodics are strictly contraindicated. indicated in cases of glaucoma, prostatic hypertrophy, urination disorders, pyloric stenosis ...
  • musculotropic type antispasmodics much better tolerated, are much more frequently used, with much more limited secondary actions.
  • phloroglucinol relaxes the contracted smooth fiber regardless of the type of contraction, without other systemic effects, nor contraindication, even at high doses.
  • phloroglucinol CAS: 108-73-6, 1,3,5-trihydroxy-benzene
  • It is widely known and used, alone, as a drug active ingredient. It is therefore a musculotropic antispasmodic. It is particularly active on the digestive system and the genitourinary system. It lifts the spasm of smooth muscle fibers and thus calms the pain. It is particularly indicated for:
  • Phloroglucinol is perfectly tolerated, its side effects are nil or negligible: it was possible to note, at most, very rare skin reactions of allergic type. It is not teratogenic or mutagenic. Clinically, the widespread use of phloroglucinol has not revealed any malformation risk to date. There are no known contraindications or precautions for use except with morphine which has a spasmogenic effect.
  • the toxicity of phloroglucinol is very low. For example, it is possible to take up to eight Lyocs per day (which is 640 mg) or three 40 mg injectable ampoules per day.
  • Phloroglucinol is also used in children.
  • Paracetamol (CAS: 103-90-2; 4-acetylaminophenol) is also widely known and used as a drug active ingredient. It intervenes alone or in combination with another active ingredient such as codeine or vitamin C. To the knowledge of the inventors, it has not been associated with an antispasmodic.
  • Paracetamol is a compound particularly indicated as an analgesic and for its antipyretic properties. It is a perfectly well tolerated substance in adults and children. Of all the antipyretic analgesics, it is the most used. It has no anti-inflammatory properties and therefore does not develop any gastrotoxicity, even when taken in a chronic and high dose. Side effects are nil or negligible: at most, there have been rare cases of reversible hypersensitivity upon discontinuation of treatment.
  • Paracetamol is not teratogenic or mutagenic.
  • overdose since doses of 10 g per day must be attained, it can trigger severe hepatic toxicity.
  • This type of overdose is exceptional in that paracetamol is used and is effective without having to exceed, in the most severe cases, the dose of 4 g per day.
  • Paracetamol is used in various forms, more particularly in the form of;
  • analgesics have been judiciously excluded, such as: nonsteroidal anti-inflammatory drugs or their derivatives, known for their analgesic properties when used at a low dose but having, even at said low doses, the disadvantages of anti-inflammatory drugs ;
  • Said combination - phloroglucinol + paracetamol - also develops, quite surprisingly, in a context of antispasmodic therapy, a potentiating synergistic action of each of said phloroglucinol and paracetamol.
  • at least one of said active ingredients is used. It is the merit of the inventors to have demonstrated said synergy and therefore the great interest of the association: phloroglucinol + paracetamol.
  • the first subject of the present invention relates to a pharmaceutical composition for oral or rectal administration, which comprises, on the one hand, phloroglucinol and, on the other hand, paracetamol, in a pharmaceutically acceptable excipient.
  • a pharmaceutical composition for oral or rectal administration which comprises, on the one hand, phloroglucinol and, on the other hand, paracetamol, in a pharmaceutically acceptable excipient.
  • the two active ingredients are formulated together (a unitary form is involved); they are formulated together for oral or rectal administration.
  • the pharmaceutically acceptable excipient is suitable for such administration, orally or rectally.
  • the pharmaceutical compositions of the invention contain the two active ingredients identified above.
  • they do not contain other active principle (s).
  • the pharmaceutically acceptable excipient is not, per se, original. It is suitable for the formulation of the two active ingredients. It is adapted to the desired route of administration (oral or rectal route), to the nature of the desired dosage form.
  • the pharmaceutical compositions of the invention are available in all galenic forms suitable for oral or rectal administration. Said galenic forms may especially consist of: tablets, capsules, powders, granules, lyophilisates, drinkable solutions, syrups, suspensions and suppositories. This list is not exhaustive.
  • tablette refers to all kinds of tablets including effervescent tablets, dispersible tablets and orodispersible tablets.
  • the active ingredients in question - phloroglucinol and paracetamol - are advantageously formulated, together, in the form of effervescent tablets.
  • effervescent tablets generally generate solutions (aqueous) whose pH is between 3 and 7. They advantageously generate solutions whose pH is close to or equal to 5.
  • the effervescent tablets in question develop effervescence in a manner known per se. especially in association with their wording:
  • At least one organic acid and / or at least one organic acid salt at least one organic acid and / or at least one organic acid salt; and at least one strong base and / or at least one strong base salt.
  • Said at least one organic acid is advantageously chosen from citric acid, tartaric acid, malic acid and acetic acid; said at least one strong base salt is advantageously selected from bicarbonates and carbonates of sodium, calcium, magnesium and potassium.
  • effervescent tablets containing the two active ingredients phloroglucinol and paracetamol are particularly preferred.
  • compositions of the invention generally contain from 50 to 200 mg of phloroglucinol. They contain in particular 80, 100 or 160 mg of phloroglucinol. In the same way, they usually contain from 100 to
  • compositions advantageously 100 to 500 mg of paracetamol.
  • said compositions contain less than 500 mg of paracetamol, and especially from 100 to less than 500 mg of paracetamol.
  • the skilled person in view of the power of the action sought, is able to optimize the absolute and relative amounts of intervention of the two active ingredients. Given the potentiating synergy evidenced, it uses a lesser amount of active ingredients for an equivalent effect (but faster) or equivalent amount of use, we see a more powerful and faster action.
  • compositions of the invention are particularly recommended in the treatment of spasmodic conditions, such as spasmodic colitis, hepatic colic, nephritic colic and dysmenorrhea.
  • the present invention relates to the preparation of a pharmaceutical composition as described above.
  • Said preparation typically comprises the formulation of phloroglucinol and paracetamol together in a pharmaceutically acceptable excipient suitable for oral or rectal administration.
  • formulation is familiar to those skilled in the art.
  • the formulation techniques of the two active ingredients in question are not innovative. They essentially comprise the mixture of the two active ingredients with the appropriate excipient, with generally the different constituent elements of said excipient.
  • the present invention relates to the use of phloroglucinol and paracetamol for the preparation of a pharmaceutical composition, suitable for oral or rectal administration, for treating spasmodic conditions.
  • Said pharmaceutical composition advantageously consists of a dosage form, as specified above, advantageously contains phloroglucinol and paracetamol in the amounts indicated above.
  • Effervescent tablets of the invention were prepared by combining, respectively, 80, 100 and 160 mg of phloroglucinol with 125, 250, 400, 500, 750 and 1000 mg of paracetamol in a pharmaceutically acceptable excipent containing:
  • Such tablets generate solutions at a pH of 5.
  • the spasmodic and painful syndrome caused by the intraperitoneal injection of 0.25 ml of the solution of phenylbenzoquinone, is characterized by posterior leg stretching and torsion of the dorso-abdominal musculature, which is recorded for a period of 30 min, starting with 15 min after phenylbenzoquinone administration .
  • test substance is administered by oesophageal tube 30 min before phenylbenzoquinone.
  • compositions of the invention such phloroglucinol lyocs and such effervescent tablets of paracetamol were dissolved and dissolved together.
  • the solution that contains the two active ingredients also has a pH of 5.
  • results are expressed as percentage inhibition of spasm and pain compared with control animals receiving only 20 ml / kg of distilled water.

Abstract

The invention relates to a pharmaceutical composition for oral or rectal administration, that contains phloroglucinol and paracetamol in a pharmaceutically acceptable carrier. The inventors have evidenced a synergy developed by these two active ingredients in antispasmodic therapy.

Description

Composition pharmaceutique renfermant du phloroglucinoi et du paracétamol Pharmaceutical composition containing phloroglucinol and paracetamol
La présente invention a pour objet une composition pharmaceutique renfermant un antispasmodique (le phoroglucinol) et un antalgique (le paracétamoi). Ladite composition, convenant à l'administration par voie orale ou rectale, est particulièrement efficace en thérapie antispasmodique.The present invention relates to a pharmaceutical composition containing an antispasmodic (phoroglucinol) and an analgesic (paracetamoi). Said composition, suitable for oral or rectal administration, is particularly effective in antispasmodic therapy.
Le spasme est une contraction involontaire, subite, intense et très douloureuse. Elle peut être d'origine rénale dans le cas de coliques néphrétiques, d'origine hépatique dans le cas de coliques hépatiques, d'origine intestinale dans les cas de spasmes intestinaux et de colites spasmodiques, d'origine gynécologique dans le cas de dysménorrhées.Spasm is an involuntary contraction, sudden, intense and very painful. It can be of renal origin in the case of renal colic, of hepatic origin in the case of hepatic colic, of intestinal origin in cases of intestinal spasm and spasmodic colitis, of gynecological origin in the case of dysmenorrhea.
Quelle qu'en soit l'origine, le spasme s'accompagne d'une douleur extrêmement intense et persistante. II existe deux types d'antispasmodique :Whatever the origin, spasm is accompanied by extremely intense and persistent pain. There are two types of antispasmodic:
- les antispasmodiques neurotropes tels l'atropine et ses dérivés, la scopolamine, les ammoniums quaternaires comme l'iodure de tiémonium, le bromure de butylhyoscine... etneurotropic antispasmodics such as atropine and its derivatives, scopolamine, quaternary ammoniums such as tiemonium iodide, butylhyoscine bromide ... and
- les antispasmodiques musculotropes tels la papavérine, la mébévirine, la trimébutine, le bromure de pinavérium, le phloroglucinoi et dérivés...musculotropic antispasmodics such as papaverine, mebevirine, trimebutine, pinaverium bromide, phloroglucinol and derivatives thereof
Les antispasmodiques neurotropes sont moins utilisés du fait des effets indésirables qui découlent de leur action pharmacologique antimuscarinique. En effet, les récepteurs muscariniques sont très largement répandus dans une variété d'organes et de tissus périphériques et centraux. Ainsi une action pharmacologique désirée, sur le péristaltisme intestinal par exemple, est dans la plupart des cas accompagnée d'effets indésirables sur la sécrétion salivaire, le cœur, le système respiratoire, urogénital... De plus, lesdits antispasmodiques neurotropes sont strictement contre-indiqués dans les cas de glaucome, d'hypertrophie prostatique, de troubles de la miction, de sténose pylorique...Neurotropic antispasmodics are less used because of the adverse effects that result from their antimuscarinic pharmacological action. Indeed, muscarinic receptors are very widely distributed in a variety of organs and peripheral and central tissues. Thus, a desired pharmacological action, for instance on intestinal peristalsis, is in most cases accompanied by undesirable effects on salivary secretion, the heart, the respiratory system, urogenital system. Moreover, said neurotropic antispasmodics are strictly contraindicated. indicated in cases of glaucoma, prostatic hypertrophy, urination disorders, pyloric stenosis ...
Par contre, on utilise beaucoup plus fréquemment les antispasmodiques de type musculotrope, beaucoup mieux tolérés, aux actions secondaires beaucoup plus limitées. Ainsi, le phloroglucinoi relâche la fibre lisse contractée quel que soit le type de contraction, sans autres effets systémiques, ni contre-indication, même à forte dose. En référence au phloroglucinol (CAS : 108-73-6 ; trihydroxy- 1,3,5-benzène), on peut préciser ce qui suit. Il est très largement connu et utilisé, seul, en tant que principe actif de médicament. C'est donc un antispasmodique musculotrope. Il est particulièrement actif sur l'appareil digestif et le système génito-urinaire. Il lève le spasme des fibres musculaires lisses et de ce fait calme la douleur. Il est particulièrement indiqué pour :On the other hand, musculotropic type antispasmodics, much better tolerated, are much more frequently used, with much more limited secondary actions. Thus, phloroglucinol relaxes the contracted smooth fiber regardless of the type of contraction, without other systemic effects, nor contraindication, even at high doses. With reference to phloroglucinol (CAS: 108-73-6, 1,3,5-trihydroxy-benzene), the following can be stated. It is widely known and used, alone, as a drug active ingredient. It is therefore a musculotropic antispasmodic. It is particularly active on the digestive system and the genitourinary system. It lifts the spasm of smooth muscle fibers and thus calms the pain. It is particularly indicated for:
- le traitement symptomatique des douleurs liées aux troubles fonctionnels du type digestif et des voies biliaires ; - le traitement des manifestations spasmodiques et douloureuses aiguës des voies urinaires : coliques néphrétiques ; le traitement symptomatique des manifestations spasmodiques douloureuses et gynécologiques ;- symptomatic treatment of pain related to functional disorders of the digestive tract and bile ducts; - the treatment of acute spasmodic and painful manifestations of the urinary tract: renal colic; symptomatic treatment of painful and gynecological spasmodic manifestations;
- le traitement adjuvant des contractions au cours de la grossesse en association au repos.- adjuvant treatment of contractions during pregnancy in combination with rest.
Le phloroglucinol est parfaitement toléré, ses effets secondaires sont nuls ou négligeables : on a pu noter, tout au plus, quelques très rares réactions cutanées de type allergique. Il n'est pas tératogène, ni mutagène. En clinique, l'utilisation très répandue du phloroglucinol n'a révélé aucun risque malformatif à ce jour. On ne lui connaît pas de contre- indication ni de précaution d'emploi particulières, excepté avec la morphine qui a un effet spasmogène.Phloroglucinol is perfectly tolerated, its side effects are nil or negligible: it was possible to note, at most, very rare skin reactions of allergic type. It is not teratogenic or mutagenic. Clinically, the widespread use of phloroglucinol has not revealed any malformation risk to date. There are no known contraindications or precautions for use except with morphine which has a spasmogenic effect.
Il est utilisé sous différentes formes, plus particulièrement sous la forme de : - comprimés enrobés,It is used in various forms, more particularly in the form of: - coated tablets,
- lyophilisats (Lyocs),lyophilisates (Lyocs),
- comprimés effervescents,- effervescent tablets,
- solutions injectables.- injectable solutions.
La toxicité du phloroglucinol est très faible. A titre d'exemple, il est possible de prendre jusqu'à huit Lyocs par jour (ce qui représente 640 mg) ou trois ampoules injectables de 40 mg par voie veineuse par jour.The toxicity of phloroglucinol is very low. For example, it is possible to take up to eight Lyocs per day (which is 640 mg) or three 40 mg injectable ampoules per day.
Le phloroglucinol est également utilisé chez l'enfant. Le paracétamol (CAS : 103-90-2 ; 4-acétylaminophénol) est lui aussi très largement connu et utilisé en tant que principe actif de médicament. Il intervient seul ou associé à un autre principe actif tel la codéine ou la vitamine C. A la connaissance des inventeurs, il n'a pas été associé à un antispasmodique. Il existe toutefois une publication - THE EUROPEAN JOURNAL OF HOSPITAL PHARMACY SCIENCE, vol. 12, n° 5, 2006, pages 91-95 - qui présente les résultats d'une étude physico- chimique de stabilité et de compatibilité du paracétamol et du phloroglucinol, formulés ensemble, au sein de solutions pour injection intraveineuse. Cette publication, strictement analytique, ne mentionne que l'administration par voie intraveineuse, ne contient aucun résultat de tests pharmacologiques, ne décrit ni ne suggère aucune synergie potentialisatrice (voir plus loin).Phloroglucinol is also used in children. Paracetamol (CAS: 103-90-2; 4-acetylaminophenol) is also widely known and used as a drug active ingredient. It intervenes alone or in combination with another active ingredient such as codeine or vitamin C. To the knowledge of the inventors, it has not been associated with an antispasmodic. There is however a publication - THE EUROPEAN JOURNAL OF HOSPITAL PHARMACY SCIENCE, vol. 12, No. 5, 2006, pages 91-95 - which presents the results of a physico-chemical study of stability and compatibility of paracetamol and phloroglucinol, formulated together, in solutions for intravenous injection. This strictly analytical publication only mentions intravenous administration, does not contain any results of pharmacological tests, nor does it describe or suggest any potentiating synergy (see below).
Le paracétamol est un composé particulièrement indiqué comme analgésique et pour ses propriétés antipyrétiques. C'est une substance parfaitement bien tolérée chez l'adulte et chez l'enfant. De tous les antalgiques antipyrétiques, c'est le plus utilisé. Il ne possède pas de propriétés anti-inflammatoires et il ne développe donc aucune gastrotoxicité, même pris de façon chronique et à forte dose. Ses effets secondaires sont nuls ou négligeables : on a pu noter, tout au plus, quelques rares cas d'hypersensibilité réversibles à l'arrêt du traitement.Paracetamol is a compound particularly indicated as an analgesic and for its antipyretic properties. It is a perfectly well tolerated substance in adults and children. Of all the antipyretic analgesics, it is the most used. It has no anti-inflammatory properties and therefore does not develop any gastrotoxicity, even when taken in a chronic and high dose. Side effects are nil or negligible: at most, there have been rare cases of reversible hypersensitivity upon discontinuation of treatment.
Le paracétamol n'est pas tératogène, ni mutagène. Par contre, à des très fortes doses, correspondantes à des cas de très larges surdosages (puisqu'il faut atteindre des doses de 10 g par jour), il peut déclencher une toxicité hépatique sévère. Ce type de surdosage est exceptionnel dans la mesure où le paracétamol est utilisé et est efficace sans avoir à dépasser, dans les cas les plus sévères, la dose de 4 g par jour.Paracetamol is not teratogenic or mutagenic. On the other hand, at very high doses, corresponding to cases of very large overdoses (since doses of 10 g per day must be attained), it can trigger severe hepatic toxicity. This type of overdose is exceptional in that paracetamol is used and is effective without having to exceed, in the most severe cases, the dose of 4 g per day.
Le paracétamol est utilisé sous différentes formes, plus particulièrement sous la forme de ;Paracetamol is used in various forms, more particularly in the form of;
- comprimés, notamment comprimés effervescents et comprimés orodispersibles, - solutions buvables pédiatriques,- tablets, especially effervescent tablets and orodispersible tablets, - pediatric oral solutions,
- poudres effervescentes,- effervescent powders,
- suppositoires,- suppositories,
- solutés injectables.- injectable solutions.
Dans un tel contexte, les inventeurs proposent d'associer lesdits deux principes actifs connus :In such a context, the inventors propose associating said two known active ingredients:
- le phloroglucinol, d'une part, et - le paracétamol, d'autre part.- phloroglucinol, on the one hand, and - Paracetamol, on the other hand.
Le choix du paracétamol, parmi les antalgiques existants, est particulièrement avantageux. D'autres antalgiques ont été judicieusement écartés, comme : - les anti-inflammatoires non stéroïdiens ou leurs dérivés, connus pour leurs propriétés antalgiques lorsqu'ils sont utilisés à faible dose mais présentant, même auxdites faibles doses, les inconvénients d'anti-inflammatoires ;The choice of paracetamol among the existing analgesics is particularly advantageous. Other analgesics have been judiciously excluded, such as: nonsteroidal anti-inflammatory drugs or their derivatives, known for their analgesic properties when used at a low dose but having, even at said low doses, the disadvantages of anti-inflammatory drugs ;
- l'aspirine (acide acétylsalicylique), non seulement gastrotoxique mais également antiagrégant plaquettaire ;- aspirin (acetylsalicylic acid), not only gastrotoxic but also platelet antiaggregant;
- le tramadol, à action centrale, susceptible de provoquer un phénomène de dépendance et un syndrome de sevrage ;- centrally acting tramadol, which may provoke a phenomenon of dependence and a withdrawal syndrome;
- le dextropropoxyphène, antalgique opioïde.- dextropropoxyphene, opioid analgesic.
Ladite association - phloroglucinol + paracétamol - développe par ailleurs, de façon tout à fait surprenante, dans un contexte de thérapie antispasmodique, une synergie potentialisatrice des actions de chacun desdits phloroglucinol et paracétamol. Pour l'obtention d'une efficacité équivalente, dans le cadre de l'association, on utilise moins d'au moins l'un desdits principes actifs. II est du mérite des inventeurs d'avoir mis en évidence ladite synergie et donc le grand intérêt de l'association : phloroglucinol + paracétamol.Said combination - phloroglucinol + paracetamol - also develops, quite surprisingly, in a context of antispasmodic therapy, a potentiating synergistic action of each of said phloroglucinol and paracetamol. In order to obtain an equivalent efficiency, in the context of the combination, at least one of said active ingredients is used. It is the merit of the inventors to have demonstrated said synergy and therefore the great interest of the association: phloroglucinol + paracetamol.
Le premier objet de la présente invention concerne une composition pharmaceutique, pour administration par voie orale ou rectale, qui comprend, d'une part, du phloroglucinol et, d'autre part, du paracétamol, dans un excipient pharmaceutiquement acceptable. Au sein de ladite composition, les deux principes actifs sont formulés ensemble (une forme unitaire est en cause) ; ils sont formulés ensemble pour une administration par voie orale ou rectale. L'excipient pharmaceutiquement acceptable convient pour une telle administration, par voie orale ou rectale.The first subject of the present invention relates to a pharmaceutical composition for oral or rectal administration, which comprises, on the one hand, phloroglucinol and, on the other hand, paracetamol, in a pharmaceutically acceptable excipient. Within said composition, the two active ingredients are formulated together (a unitary form is involved); they are formulated together for oral or rectal administration. The pharmaceutically acceptable excipient is suitable for such administration, orally or rectally.
Les compositions pharmaceutiques de l'invention renferment les deux principes actifs identifiés ci-dessus. Avantageusement, elles ne renferment pas d'autre(s) principe(s) actif(s). Toutefois, l'intervention en leur sein d'au moins un autre principe actif ne saurait en aucun cas être exclue. L'excipient pharmaceutiquement acceptable n'est pas, per se, original. Il convient à la formulation des deux principes actifs. Il est adapté à la voie d'administration souhaitée (voie orale ou voie rectale), à la nature de la forme galénique souhaitée. Les compositions pharmaceutiques de l'invention se déclinent sous toutes formes galéniques convenant à l'administration par voie orale ou rectale. Lesdites formes galéniques peuvent notamment consister en : des comprimés, des gélules, des poudres, des granulés, des lyophilisats, des solutés buvables, des sirops, des suspensions et des suppositoires. Cette liste n'est pas exhaustive.The pharmaceutical compositions of the invention contain the two active ingredients identified above. Advantageously, they do not contain other active principle (s). However, the intervention within them of at least one other active principle can not be excluded under any circumstances. The pharmaceutically acceptable excipient is not, per se, original. It is suitable for the formulation of the two active ingredients. It is adapted to the desired route of administration (oral or rectal route), to the nature of the desired dosage form. The pharmaceutical compositions of the invention are available in all galenic forms suitable for oral or rectal administration. Said galenic forms may especially consist of: tablets, capsules, powders, granules, lyophilisates, drinkable solutions, syrups, suspensions and suppositories. This list is not exhaustive.
Le terme "comprimé" désigne toutes sortes de comprimés et notamment les comprimés effervescents, les comprimés dispersibles et les comprimés orodispersibles.The term "tablet" refers to all kinds of tablets including effervescent tablets, dispersible tablets and orodispersible tablets.
Selon l'invention, les principes actifs en cause - phloroglucinol et paracétamol - sont avantageusement formulés, ensemble, sous la forme de comprimés effervescents. De tels comprimés effervescents génèrent généralement des solutions (aqueuses) dont le pH est compris entre 3 et 7. Ils génèrent avantageusement des solutions dont le pH est voisin de ou égal à 5. Les comprimés effervescents en cause développent l'effervescence de façon connue per se, notamment de par l'association dans leur formulation :According to the invention, the active ingredients in question - phloroglucinol and paracetamol - are advantageously formulated, together, in the form of effervescent tablets. Such effervescent tablets generally generate solutions (aqueous) whose pH is between 3 and 7. They advantageously generate solutions whose pH is close to or equal to 5. The effervescent tablets in question develop effervescence in a manner known per se. especially in association with their wording:
- d'au moins un acide organique et/ou d'au moins un sel d'acide organique ; et - d'au moins une base forte et/ou d'au moins un sel de base forte.at least one organic acid and / or at least one organic acid salt; and at least one strong base and / or at least one strong base salt.
Ledit au moins un acide organique est avantageusement choisi parmi l'acide citrique, l'acide tartrique, l'acide malique et l'acide acétique ; ledit au moins un sel de base forte est avantageusement choisi parmi les bicarbonates et carbonates de sodium, calcium, magnésium et potassium. Dans le cadre de la présente invention, les comprimés effervescents (renfermant les deux principes actifs ; phloroglucinol et paracétamol) sont particulièrement préférés.Said at least one organic acid is advantageously chosen from citric acid, tartaric acid, malic acid and acetic acid; said at least one strong base salt is advantageously selected from bicarbonates and carbonates of sodium, calcium, magnesium and potassium. In the context of the present invention, effervescent tablets (containing the two active ingredients phloroglucinol and paracetamol) are particularly preferred.
Les compositions pharmaceutiques de l'invention renferment généralement de 50 à 200 mg de phloroglucinol. Elles renferment notamment 80, 100 ou 160 mg de phloroglucinol. De la même façon, elles renferment généralement de 100 àThe pharmaceutical compositions of the invention generally contain from 50 to 200 mg of phloroglucinol. They contain in particular 80, 100 or 160 mg of phloroglucinol. In the same way, they usually contain from 100 to
1000 mg de paracétamol, avantageusement de 100 à 500 mg de paracétamol. Selon une variante préférée, lesdites compositions renferment moins de 500 mg de paracétamol, et notamment de 100 à moins de 500 mg de paracétamol.1000 mg of paracetamol, advantageously 100 to 500 mg of paracetamol. According to a preferred variant, said compositions contain less than 500 mg of paracetamol, and especially from 100 to less than 500 mg of paracetamol.
L'homme du métier, au vu de la puissance de l'action recherchée, est à même d'optimiser les quantités d'intervention absolues et relatives des deux principes actifs. Compte tenu de la synergie potentialisatrice mise en évidence, on utilise une moindre quantité de principes actifs pour un effet équivalent (mais plus rapide) ou, à quantité d'utilisation équivalente, on observe une action plus puissante et plus rapide.The skilled person, in view of the power of the action sought, is able to optimize the absolute and relative amounts of intervention of the two active ingredients. Given the potentiating synergy evidenced, it uses a lesser amount of active ingredients for an equivalent effect (but faster) or equivalent amount of use, we see a more powerful and faster action.
Les compositions pharmaceutiques de l'invention, préconisées en thérapie antispasmodique, sont tout particulièrement préconisées dans le traitement des affections spasmodiques, telles les colites spasmodiques, les coliques hépatiques, les coliques néphrétiques et les dysménorrhées.The pharmaceutical compositions of the invention, recommended in antispasmodic therapy, are particularly recommended in the treatment of spasmodic conditions, such as spasmodic colitis, hepatic colic, nephritic colic and dysmenorrhea.
Selon un autre de ses objets, la présente invention concerne la préparation d'une composition pharmaceutique telle que décrite ci-dessus. Ladite préparation, de façon caractéristique, comprend la formulation du phloroglucinol et du paracétamol, ensemble, dans un excipient pharmaceutiquement acceptable convenant pour une administration par voie orale ou rectale.According to another of its objects, the present invention relates to the preparation of a pharmaceutical composition as described above. Said preparation typically comprises the formulation of phloroglucinol and paracetamol together in a pharmaceutically acceptable excipient suitable for oral or rectal administration.
Le terme de formulation est familier à l'homme du métier. Les techniques de formulation des deux principes actifs en cause ne sont pas perse novatrices. Elles comprennent essentiellement le mélange des deux principes actifs avec l'excipient adéquat, avec généralement les différents éléments constitutifs dudit excipient.The term formulation is familiar to those skilled in the art. The formulation techniques of the two active ingredients in question are not innovative. They essentially comprise the mixture of the two active ingredients with the appropriate excipient, with generally the different constituent elements of said excipient.
Selon un autre de ses aspects, la présente invention concerne l'utilisation du phloroglucinol et du paracétamol pour la préparation d'une composition pharmaceutique, convenant à l'administration par voie orale ou rectale, destinée à traiter les affections spasmodiques. Ladite composition pharmaceutique consiste avantageusement en une forme galénique, telle que précisée ci-dessus, renferme avantageusement le phloroglucinol et le paracétamol en les quantités indiquées ci-dessus. On se propose maintenant d'illustrer ci-après, de façon nullement limitative, l'invention. ExemplesIn another aspect, the present invention relates to the use of phloroglucinol and paracetamol for the preparation of a pharmaceutical composition, suitable for oral or rectal administration, for treating spasmodic conditions. Said pharmaceutical composition advantageously consists of a dosage form, as specified above, advantageously contains phloroglucinol and paracetamol in the amounts indicated above. We now propose to illustrate below, in no way limiting, the invention. Examples
a) Des comprimés effervescents de l'invention ont été préparés en associant, respectivement, 80, 100 et 160 mg de phloroglucinol à 125, 250, 400, 500, 750 et 1000 mg de paracétamol dans un excipent pharmaceutiquement acceptable renfermant :a) Effervescent tablets of the invention were prepared by combining, respectively, 80, 100 and 160 mg of phloroglucinol with 125, 250, 400, 500, 750 and 1000 mg of paracetamol in a pharmaceutically acceptable excipent containing:
- de l'acide citrique q.s.- citric acid q.s.
- du bicarbonate de sodium q.s.- sodium bicarbonate q.s.
- du docusate de sodium q.s. - de la povidone q.s.- sodium docusate q.s. - povidone q.s.
- de la saccharine sodique, et q.s.- Sodium saccharin, and q.s.
- du benzoate de sodium q.s.- sodium benzoate q.s.
De tels comprimés génèrent des solutions à un pH de 5.Such tablets generate solutions at a pH of 5.
On indique ci-après la composition massique exacte d'un comprimé effervescent de ce type :The following is the exact mass composition of an effervescent tablet of this type:
Phloroglucinol 80 mgPhloroglucinol 80 mg
Paracétamol 250 mgParacetamol 250 mg
Bicarbonate de sodium 295,2 mgSodium bicarbonate 295.2 mg
Acide citrique 215 mg Povidone 35 mgCitric acid 215 mg Povidone 35 mg
Benzoate de sodium 15,2 mgSodium benzoate 15.2 mg
Docusate de sodium 0,2 mgSodium Docusate 0.2 mg
Saccharine sodique 0,5 mg.Saccharin sodium 0.5 mg.
b) On se propose enfin d'illustrer l'intérêt de la présente invention en présentant ci-après des résultats comparatifs de tests pharmacologiques.b) It is finally proposed to illustrate the advantage of the present invention by presenting hereinafter comparative results of pharmacological tests.
Au cours desdits tests, l'activité antispasmodique et analgésique du phloroglucinol, du paracétamol, et du phloroglucinol associé au paracétamol a été évaluée à l'aide du test de SIEGMUND ou "Wrinting test". On rappelle ci-après brièvement le principe de ce test familier à l'homme de métier. L'injection intrapéritonéale de phénylbenzoquinone chez la souris provoque un spasme douloureux, qui peut être réduit par les substances antispasmodiques (médication causale) et les substances antalgiques (médication symptomatique). L'essai a été réalisé sur des lots de 10 souris mâles, de souche Swiss, d'un poids moyen de 22 g ± 2. Le syndrome spasmodique et douloureux, provoqué par l'injection intrapéritonéale de 0,25 ml de la solution de phénylbenzoquinone, se caractérise par des mouvements d'étirement des pattes postérieures et de la torsion de la musculature dorso-abdominale que l'on comptabilise pendant un laps de temps de 30 min, à partir des 15 min qui suivent l'administration de la phénylbenzoquinone.During these tests, the antispasmodic and analgesic activity of phloroglucinol, paracetamol, and phloroglucinol combined with paracetamol was evaluated using the SIEGMUND test or "Wrinting test". Briefly, hereinafter recalls the principle of this test familiar to those skilled in the art. Intraperitoneal injection of phenylbenzoquinone in mice causes painful spasm, which can be reduced by antispasmodic substances (causal medication) and analgesics (symptomatic medication). The test was carried out on batches of 10 male mice, of Swiss strain, with an average weight of 22 g ± 2. The spasmodic and painful syndrome, caused by the intraperitoneal injection of 0.25 ml of the solution of phenylbenzoquinone, is characterized by posterior leg stretching and torsion of the dorso-abdominal musculature, which is recorded for a period of 30 min, starting with 15 min after phenylbenzoquinone administration .
Un effet antispasmodique et antalgique se manifeste par une réduction du nombre des crises spasmodiques, qui est fonction de la dose. Pour chaque test, la substance à l'étude est administrée par sonde œsophagienne, 30 min avant la phénylbenzoquinone.An antispasmodic and analgesic effect is manifested by a reduction in the number of spasmodic attacks, which is a function of the dose. For each test, the test substance is administered by oesophageal tube 30 min before phenylbenzoquinone.
Pour la facilité expérimentale, il a été utilisé :For the experimental facility, it was used:
- du phloroglucinol Lyoc (lyophilisât), et - du paracétamol effervescent (comprimé) ; les deux substances étant parfaitement solubles et miscibles.- Lyoc phloroglucinol (lyophilisate), and - effervescent paracetamol (tablet); the two substances being perfectly soluble and miscible.
Pour tester les produits administrés isolément (art antérieur), des lyocs de phloroglucinol ont été dissous dans de l'eau distillée, d'une part et des comprimés effervescents de paracétamol ont été mis en solution dans de l'eau distillée (la solution obtenue présente un pH de 5), d'autre part.To test the products administered alone (prior art), phloroglucinol lyocs were dissolved in distilled water, on the one hand and effervescent tablets of paracetamol were dissolved in distilled water (the solution obtained has a pH of 5), on the other hand.
Pour tester les compositions pharmaceutiques de l'invention, on a dissous et mis en solution, ensemble, de tels lyocs de phloroglucinol et de tels comprimés effervescents de paracétamol. La solution qui renferme les deux principes actifs présente elle aussi un pH de 5.To test the pharmaceutical compositions of the invention, such phloroglucinol lyocs and such effervescent tablets of paracetamol were dissolved and dissolved together. The solution that contains the two active ingredients also has a pH of 5.
Compte tenu du métabolisme plus accéléré chez cette espèce animale, la souris, que chez l'homme, l'homme du métier, spécialiste de la pharmacologie, utilise le plus souvent des doses qui sont des multiples de la dose humaine afin de pouvoir aisément objectiver les résultats. Les résultats sont exprimés en pourcentage d'inhibition du spasme et de la douleur par rapport à des animaux témoins qui ne reçoivent que 20 ml/kg d'eau distillée.Given the more accelerated metabolism in this animal species, the mouse, than in humans, the skilled person, specialist in pharmacology, most often uses doses that are multiples of the human dose in order to easily objectify the results. The results are expressed as percentage inhibition of spasm and pain compared with control animals receiving only 20 ml / kg of distilled water.
Lesdits résultats sont consignés dans le tableau ci-après, accompagnés du calcul statistique. TableauThese results are recorded in the table below, together with the statistical calculation. Board
Figure imgf000010_0001
Figure imgf000010_0001
*p = 0,05 **p = 0,01 ***p = 0,001* p = 0.05 ** p = 0.01 *** p = 0.001
L'examen de ces résultats montre que, quelles que soient les doses utilisées, on met toujours en évidence une synergie potentialisatrice (de 40 à 50 %) de l'association phloroglucinol + paracétamol, sur le spasme douloureux. Cette synergie est déjà statistiquement hautement significative dès les faibles doses (p = 0,001) et elle augmente toujours avec l'augmentation des doses.Examination of these results shows that, whatever the doses used, one always highlights a potentiating synergy (from 40 to 50%) of the association phloroglucinol + paracetamol, on the painful spasm. This synergy is already statistically highly significant at low doses (p = 0.001) and always increases with increasing doses.
On note que, pour une association de 120 mg de phloroglucinol et de 50 mg de paracétamol (par kg), il n'y a aucune contraction. Les animaux sont totalement protégés (système saturé).It is noted that for a combination of 120 mg of phloroglucinol and 50 mg of paracetamol (per kg), there is no contraction. The animals are totally protected (saturated system).
Les chiffres ci-dessus démontrent assurément le caractère non évident de l'invention ainsi que son grand intérêt. The figures above undoubtedly demonstrate the non-obvious nature of the invention as well as its great interest.

Claims

REVENDICATIONS
1. Composition pharmaceutique, pour administration par voie orale ou rectale, renfermant du phloroglucinol et du paracétamol dans un excipient pharmaceutiquement acceptable.A pharmaceutical composition, for oral or rectal administration, containing phloroglucinol and paracetamol in a pharmaceutically acceptable excipient.
2. Composition pharmaceutique selon la revendication 1, caractérisé en ce qu'elle se présente sous une forme galénique choisie parmi les comprimés, les gélules, les poudres, les granulés, les lyophilisats, les solutés buvables, les sirops, les suspensions et les suppositoires.2. Pharmaceutical composition according to claim 1, characterized in that it is in a dosage form chosen from tablets, capsules, powders, granules, lyophilisates, drinkable solutions, syrups, suspensions and suppositories. .
3. Composition pharmaceutique selon la revendication 1 ou 2, caractérisée en ce qu'elle se présente sous la forme de comprimés effervescents.3. Pharmaceutical composition according to claim 1 or 2, characterized in that it is in the form of effervescent tablets.
4. Composition pharmaceutique selon la revendication 3, caractérisée en ce que lesdits comprimés effervescents renferment au moins un acide organique et/ou au moins un sel d'acide organique, ledit acide organique étant avantageusement choisi parmi l'acide citrique, l'acide tartrique, l'acide malique et l'acide acétique, et au moins une base forte et/ou au moins un sel d'une base forte, ledit au moins un sel de base forte étant avantageusement choisi parmi les bicarbonates et carbonates de sodium, calcium, magnésium et potassium .4. Pharmaceutical composition according to claim 3, characterized in that the said effervescent tablets contain at least one organic acid and / or at least one organic acid salt, the said organic acid being advantageously chosen from citric acid and tartaric acid. , malic acid and acetic acid, and at least one strong base and / or at least one salt of a strong base, said at least one strong base salt being advantageously chosen from bicarbonates and sodium carbonates, calcium , magnesium and potassium.
5. Composition pharmaceutique selon l'une quelconque des revendications 1 à 4, caractérisée en ce qu'elle renferme le phloroglucinol à une dose comprise entre 50 et 200 mg, notamment à une dose de 80, 100 ou 160 mg.5. Pharmaceutical composition according to any one of claims 1 to 4, characterized in that it contains phloroglucinol at a dose of between 50 and 200 mg, especially at a dose of 80, 100 or 160 mg.
6. Composition pharmaceutique selon l'une quelconque des revendications 1 à 5, caractérisée en ce qu'elle renferme ledit paracétamol à une teneur comprise entre 100 et 1 000 mg, avantageusement entre 100 et 500 mg.6. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that it contains said paracetamol at a content between 100 and 1000 mg, preferably between 100 and 500 mg.
7. Composition pharmaceutique selon l'une quelconque des revendications 1 à 6, pour le traitement des affections spasmodiques, et notamment pour le traitement des colites spasmodiques, des coliques hépatiques, les coliques néphrétiques et les dysménorrhées.7. Pharmaceutical composition according to any one of claims 1 to 6, for the treatment of spasmodic conditions, and in particular for the treatment of spasmodic colitis, hepatic colic, nephritic colic and dysmenorrhea.
8. Préparation d'une composition pharmaceutique selon l'une quelconque des revendications 1 à 7, caractérisée en ce qu'elle comprend la formulation desdits phloroglucinol et paracétamol, ensemble, dans un excipient pharmaceutiquement acceptable convenant à une administration par voie orale ou rectale.8. Preparation of a pharmaceutical composition according to any one of claims 1 to 7, characterized in that it comprises the formulation of said phloroglucinol and paracetamol, together, in a pharmaceutically acceptable excipient suitable for oral or rectal administration.
9. Utilisation du phloroglucinol et du paracétamol pour la préparation d'une composition pharmaceutique, convenant à l'administration par voie orale ou rectale, destinée à traiter les affections spasmodiques. 9. Use of phloroglucinol and paracetamol for the preparation of a pharmaceutical composition, suitable for oral or rectal administration, for treating spasmodic conditions.
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ITMI20092151A1 (en) * 2009-12-04 2011-06-05 Diverdrugs Sl PHARMACEUTICAL PREPARATIONS INCLUDING FLOROGLUCINOL AND / OR ITS NON-STEROID ANTI-INFLAMMATORY DERIVATIVES AND DRUGS AND THEIR USE IN THE TREATMENT AND / OR PREVENTION OF THE PAIN SYNDROMES OF THE FEMALE GENITAL SYSTEM.
WO2011067663A1 (en) * 2009-12-04 2011-06-09 Diverdrugs Sl Pharmaceutical preparations comprising phloroglucinol and/or derivatives thereof and some non-steroidal anti-inflammatory drugs and their use in the treatment and/or prevention of pain syndromes of the feminine genital system

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ZA200905440B (en) 2010-10-27
MA31227B1 (en) 2010-03-01
FR2912654B1 (en) 2009-12-25
FR2912654A1 (en) 2008-08-22
US8148425B2 (en) 2012-04-03
MX2009008813A (en) 2010-03-03
CA2678042C (en) 2016-05-31
BRPI0810057A2 (en) 2014-10-21
US20100168238A1 (en) 2010-07-01
EP2120901A1 (en) 2009-11-25

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